medigraphic.com
Academia Mexicana de Neurología, A.C.

2015, Number 6

<< Back Next >>

Rev Mex Neuroci 2015; 16 (6)

Congenital malformations in rats prenatally exposed to valproic acid and their relationship with Purkinje cells counts

Puig-Lagunes ÁA, Velazco-Cercas E, Zamora-Bello II, Beltrán-Parrazal L, Morgado-Valle C, Manzo J, López-Meraz ML

Language: Spanish
References: 42
Page: 28-40
PDF size: 1208.84 Kb.


ABSTRACT

Introduction: Valproic acid (VPA) is a commonly used drug for the treatment of epilepsy, acute manias and bipolar disorder. It is known that the use of AVP during pregnancy an produce congenital malformations, the fetal valproate syndrome and augment the risk for autism. This disorders haven been modeled in the laboratory by injecting VPA during the embryonic period rats, inducing additionally modifications in the cerebellar anatomy similar to those detected in people with autism.
Objective: The goal of this study was to describe some congenital malformations observed in rats exposed prenatally to VPA and its correlation with the number of Purkinje cells from the cerebellar vermis.
Methods: VPA (600mg/kg) was applied to pregnant rats during the 12th embrionic day; control rats were injected with saline during the same day. Rats with malformations and control rats were euthanized during the postnatal day 40 and the number of Purkinje cells was determined in sagittal sections from the medial vermis stained with Nissl technique.
Results: The prenatal exposure to AVP produced different severity of tail malformations and toe polydactyly, as well as a decrease in the number of Purkinje cells in the lobules VI, VII, VIII y X. A lineal positive correlation between the malformation severity and the number of Purkinje cells was observed in the lobule VIII-B; however, no correlation was detected between those parameters in any additional lobe.
Conclusion: There is not correlation between the severity of the malformations produced by VPA and the decrease in the number of Purkinje cells. These findings are relevant for a better understanding of the VPA experimental model in the rat.


REFERENCES

  1. Dufour-Rainfray D, Vourc’h P, Tourlet S, Guilloteau D, Chalon S, Andres CR. Fetal exposure to teratogens: Evidence of genes involved in autism. Neurosci Biobehav Rev 2011; 35:1254–1265.

  2. Faiella A, Wernig M, Consalez GG. et al.. A mouse model for valproate teratogenicity: parental effects, homeotic transformations, and altered HOX expression. Hum Mol Genet 2000; 9:227-236.

  3. Lagace DC, O’Brien WT, Gurvich N, Nachtigal MW, Klein PS. Valproic acid: how it works. Or not. Clin Neurosci Res 2004;4: 215–225.

  4. Kini U. Fetal valproate syndrome: a review. Paediatr Perinat Drug Ther 2006;7:123-130.

  5. Moore SJ, Turnpenny P, Quinn A, Glover S, Llovd DJ, Montgomerv Dean JCS. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet 2000; 37:489-497.

  6. Meador K, Reynolds MW, Crean S, Fahrbach K, Probst C. Pregnancy outcomes in women with epilepsy: A systematic review and meta-analysis of published pregnancy registries and cohorts. Epilepsy 2008; 8:1–13.

  7. Bromley RL, Mawer RL, Clayton-Smith J, Baker GA. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology 2008; 71:1923-1924.

  8. Clayton-Smith J, Donnai D. Fetal valproate syndrome. J Med Genet 1995; 32:724-727

  9. Rasalam AD, Hailey H, Williams JH, Moore SJ, Turnpenny PD, Lloyd DJ. et al. Characteristics of fetal anticonvulsant syndrome associated autistic disorder. Dev. Med. Child Neurol 2005; 47:551–555.

  10. Ornoy A. Valproic acid in pregnancy: How much are we endangering the embryo and fetus? Reprod Toxicol 2009; 28:1–10.

  11. Allen G. The cerebellum in autism. Clinical Neuropsychiatry. 2005; 6:321-337.

  12. Allen G and Courchesne E. Differential Effects of Developmental Cerebellar Abnormality on Cognitive and Motor Functions in the Cerebellum: An fMRI Study of Autism. Am J Psychiatry 2003; 160:262– 273.

  13. Courchesne E, Karns C, Davis H, Ziccardi R, Carper R, Tigue Z, Chisum H, et al. Unusual brain growth patterns in early life in patients with autistic disorder: An MRI study. Neurology 2001; 57:245-254.

  14. Hashimoto T, Tayama M, Murakawa K, Yoshimoto T, Miyazaki M, Harada M. et al. Development of the brainstem and cerebellum in autistic patients. J Autism Dev Disord 1995; 25:1–18.

  15. Courchesne E, Townsend J, Saitoh O et al. The brain in infantile autism: posterior fossa structures are abnormal. Neurology 1994; 44:214– 223.

  16. Courchesne E, Chisum H, Towsend J. Activity-dependent brain changes in development. Implications for psychopathology. Dev Psychopathol 1994b; 6:697-722.

  17. Courchesne E, Towsend J, Chase C. Neurodevelopmental principles guide research on developmental psychopathologies. En: Cicchetti D y Cohen D, eds. A manual of developmental Psychopathology. New York: John Wiley. 1994c: 195-226.

  18. Rout UK, Dhossche DM. A pathogenetic model of autism involving Purkinje cell loss through anti-GAD antibodies. Med Hypotheses 2008; 71:218–221.

  19. Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M, Rutter M, Lantos PA. Clinicopathological study of autism. Brain 1998; 121:889–905.

  20. Lee M, Martin-Ruiz C, Graham A, Court J, Jaros E, Perry R et al. Nicotinic receptor abnormalities in the cerebellar cortex in autism. Brain 2002; 15:1483–1495.

  21. Whitney ER, Kemper TL, Bauman ML, Rosene DL, Blatt GJ. Cerebellar Purkinje Cells are Reduced in a Subpopulation of Autistic Brains: A Stereological Experiment Using Calbindin-D28k. Cerebellum 2008; 7:406–416.

  22. Fatemi SH, Halt AR, Realmuto G, Earle J, Kist DA, Thuras P, Merz A. Purkinje Cell Size Is Reduced in Cerebellum of Patients with Autism. Celular and Molecular Neurobiology 2002; 22:171-175.

  23. Ingram JL, Peckham SM, Tisdale B, Rodier PM. Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism. Neurotoxicol Teratol 2000; 22:319–324.

  24. Schneider T, Przewlocki R. Behavioral alterations in rats prenatally exposed to valproic acid: animal model of autism. Neuropsychopharmacology 2005; 30:80–9.

  25. Schneider T, Roman A, Basta-Kaim A, Kubera M, Budziszewska B, Schneider K et al. Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid. Psychoneuroendocrinology 2008; 33:728–40.

  26. Bambini-Junior V, Rodrigues L, Behr GA, Fonseca Moreira JC, Riesgo R, Gottfried C. Animal model of autism induced by prenatal exposure to valproate: Behavioral changes and liver parameters. Brain Res 2011; 1408:8–16.

  27. Kim KC, Kim P, Go HS, Choi CS, Yang SI, Cheong JH, Shin CY, Ko KH. The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats. Toxicol Lett 2011; 201:137–142.

  28. Roullet FI, Lai JKY, Foster JA. In utero exposure to valproic acid and autism — A current review of clinical and animal studies. Neurotoxicol and Teratol 2013; 36: 47–56.

  29. Saft P, Toledo-Cardenas R, Coria-Avila GA, Perez-Pouchoulen M, Brug B, Hernandez ME et al. Characterization of four types of tail abnormalities in rats treated prenatally with valproic acid. Revista eNeurobiología 2014; 5:1-6.

  30. Ogawa T, Kuwagata M, Hori Y, Shioda S. Valproate-induced developmental neurotoxicity is affected by maternal conditions including shipping stress and environmental change during early pregnancy. Toxicol Lett 2007; 174:18–24.

  31. Rodier PM, Ingram JL, Tisdale B, Croog VJ. Linking etiologies in humans and animal models: studies of autism. Reprod Toxicol 1997; 11:417-22.

  32. Chen G, Yuan PX, Jiang YM, Huang LD, Manji HK. Valproate robustly enhances AP-1 mediated gene expression. Brain Res Mol Brain Res 1999; 64:52–58.

  33. Chen B, Wang JF, Hill BC, Young LT. Lithium and valproate differentially regulate brain regional expression of phosphorylated CREB and c-FOS. Brain Res Mol Brain Res 1999; 70:45–53.

  34. Fuller LC, Cornelius SK, Murphy CW, Wiens DJ. Neural crest cell motility in valproic acid. Reprod Toxicol 2002; 16:825–39.

  35. Kim KC, Kim P, Go HS, Choi CS, Park JH, Kim HJ et al. Male-specific alteration in excitatory postsynaptic development and social interaction in prenatal valproic acid exposure model of autism spectrum disorder. J. Neurochem 2013; 124:832-843.

  36. Lindhout D, Omtzigt JG. Pregnancy and the risk of teratogenicity. Epilepsia 1992;33:41–48.

  37. Courchesne E. Brainstem, cerebellar and limbic neuroanatomical abnormalities in autism. Curr Opin Neurobiol 1995; 7:269–278.

  38. Courchesne E, Redcay E, Kennedy DP. The autistic brain: birth through adulthood. Curr Opin Neurol 2004; 17:489-496.

  39. Skefos J, Cummings C, Enzer K, Holiday J, Weed K. et al. Regional Alterations in Purkinje Cell Density in Patients with Autism. PLoS ONE 2014; 9:1255-1255.

  40. Courchesne E. Infante autism part 2. A new neuro-developmental model. Pediatr Int 1995; 10:141- 154.

  41. Rapin I. Autism in search of a home in the brain. Neurology 1999; 52:902-904.

  42. Courchesne E. New evidence of cerebellar and brainstem hypoplasia in autistic infants, children and adolescents. J Autism Dev Disord 1995; 25:19-22.




2020     |     www.medigraphic.com